2-substituted heterocyclic sulfonamides

ABSTRACT

The present disclosure describes novel compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The present compounds and compositions may also be useful against a variety of disorders including, for example, multi-drug resistance, human immunodeficiency virus (HIV), cardiac injury, and neurological disorders, and may be useful for controlling parasites and invoking immunosuppression.

CROSS REFERENCE

This application claims priority under Title 35, United States Code §119(e) from Provisional Application Ser. No. 60/102,539, filed Sep. 30,1998.

FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions whichare particularly useful for treating hair loss in mammals, includingarresting and/or reversing hair loss and promoting hair growth. Thepresent compounds and compositions may also be useful against a varietyof disorders including, for example, multi-drug resistance, humanimmunodeficiency virus (HIV), cardiac injury, and neurologicaldisorders, and may be useful for controlling parasites and invokingimmunosuppression.

BACKGROUND OF THE INVENTION

Hair loss is a common problem which occurs, for example, through naturalprocesses or is often chemically promoted through the use of certaintherapeutic drugs designed to alleviate conditions such as cancer. Oftensuch hair loss is accompanied by lack of hair regrowth which causespartial or full baldness. Such baldness is cosmetically unappealing, andis particularly distressing to the person experiencing the hair loss.

As is well-known in the art, hair growth occurs by a cycle of activitywhich involves alternating periods of growth and rest. This cycle isoften divided into three main stages which are known as anagen, catagen,and telogen. Anagen is the growth phase of the cycle and may becharacterized by penetration of the hair follicle deep into the dermiswith rapid proliferation of cells which are differentiating to formhair. The next phase is catagen, which is a transitional stage marked bythe cessation of cell division, and during which the hair follicleregresses through the dermis and hair growth is ceased. The next phase,telogen, is often characterized as the resting stage during which theregressed follicle contains a germ with tightly packed dermal papillacells. At telogen, the initiation of a new anagen phase is caused byrapid cell proliferation in the germ, expansion of the dermal papilla,and elaboration of basement membrane components. This cycle is repeatedthroughout hair growth. Wherein hair growth ceases, most of the hairfollicles reside in telogen and anagen is not engaged, thus causing theonset of full or partial baldness.

There have been many attempts in the literature to invoke the regrowthof hair by, for example, the promotion or prolongation of anagen.Currently, there are two drugs approved by the United States Food andDrug Administration for the treatment of male pattern baldness: topicalminoxidil (marketed as Rogaine® by Pharmacia & Upjohn), and oralfinasteride (marketed as Propecia® by Merck & Co., Inc.).

There are conflicting reports, however, regarding the ability ofminoxidil to grow hair. In fact, early clinical studies investigatingdecreased blood pressure via the use of minoxidil did not even mentionhypertrichosis (hair growth) as a side effect. See Dormois et al.,“Minoxidil in Severe Hypertension: Value When Conventional Drugs HaveFailed”, American Heart Journal, Vol. 90, pp. 360-368 (1975). Indeed,the manufacturers of minoxidil have reported only limited hair growth ina portion of patients using minoxidil. See eg., Physician's DeskReference®, 49^(th) Ed. (1995), p. 2580. Furthermore, serious sideeffects of minoxidil are possible, including vasodilation (which leadsto retention of fluid around the heart and increased heart rate),difficulty in breathing, and weight gain. Physician's Desk Reference®,49^(th) Ed. (1995), p. 2581.

Furthermore, while early indicators show that Propecia® may be moreeffective than Rogaine®, patients using Propecia® are experiencinglimited hair growth. See The New England Journal of Medicine, Vol. 338,No. 9, Feb. 26, 1998. Furthermore, potential side effects of Propecia®are serious. Propecia® may cause impotence, decreased sexual drive,decreased volume of ejaculate, breast tenderness and enlargement, andhypersensitivity reactions, including lip swelling and skin rash.Furthermore, Propecia® is not indicated for women and children. In fact,women who are pregnant or potentially pregnant should not even handlecrushed or broken tablets containing the drug. See Physician's DeskReference®, 52^(th) Ed. (1998), p. 1737 and The New England Journal ofMedicine, Vol. 338, No. 9, Feb. 26, 1998.

Interestingly, the immunosuppressive agents cyclosporin A and FK506 areknown to invoke a prominent hypertrichotic side effect. See Iwabuchi etal., “Effects of Immunosuppressive Peptidyl-Prolyl cis-trans Isomerase(PPIase) Inhibitors, Cyclosporin A, FK506, Ascomycin, and Rapamycin, onHair Growth Initiation in Mouse: Immunosuppression is not Required forNew Hair Growth”, Journal of Dermatological Science, Vol. 9, pp. 64-69(1995); Yamamoto et al., “Hair Growth-Stimulating Effects of CyclosporinA and FK506, Potent Immunosuppressants”, Journal of DermatologicalScience, Vol. 7 (suppl.), pp. S47-S54 (1994); Yamamoto et al.,“Stimulation of Hair Growth by Topical Application of FK506, a PotentImmunosuppressive Agent”, Journal of Investigational Dermatology, Vol.102, pp. 160-164 (1994); Jiang et al., “Induction of Anagen in TelogenMouse Skin by Topical Application of FK506, a Potent Immunosuppressant”,Journal of Investigational Dermatology, Vol. 104, pp. 523-525 (1995);McElwee et al., “Topical FK506: A Potent Immunotherapy for AlopeciaAreata? Studies Using the Dundee Experimental Bald Rat Model”, BritishJournal of Dermatology, Vol. 137, pp. 491-497 (1997); Maurer et al.,“Hair Growth Modulation by Topical Immunophilin Ligands”, AmericanJournal of Pathology, Vol. 150, No. 4, pp. 1433-1441 (1997); and Paus etal., “Hair Growth Control by Immunosuppression”, Arch. Dermatol. Res.,Vol. 288, pp. 408-410 (1996). However, use of these compounds as hairgrowth actives may not be desirable due to their striking potency asimmunosuppressive agents.

FK506 is a complex, macrocyclic molecule having the following structure:

Stocks et al., “The Contribution to Binding of the PyranosideSubstituents in the Excised Binding Domain of FK-506”, Bioorganic &Medicinal Chemistry Letters, Vol. 4, No. 12, pp. 1457-1460 (1994).Analogs closely resembling this complex macrocycle have been disclosedas having hair growth properties in the form of, for example, alopeciaareata and/or male pattern baldness. See, e.g., Kawai et al., U.S. Pat.No. 5,541,193, assigned to Abbott Laboratories, issued Jul. 30, 1996;Asakura et al., U.S. Pat. No. 5,496,564, assigned to FujisawaPharmaceutical Co., issued Mar. 5, 1996; Baumann et al., U.S. Pat. No.5,352,671 assigned to Sandoz Ltd., issued Oct. 4, 1994; and Rupprecht etal., U.S. Pat. No. 5,550,233, assigned to Merck & Co., Inc., issued Aug.27, 1996.

However, excitement related to the hypertrichotic activities ofcyclosporin A and FK506 is somewhat quelled by the lack of reports ofhypertrichosis by various smaller, non-macrocyclic immunosuppressive andnon-immunosuppressive compounds which are less complex in structure thanFK506. See Steiner et al., WO 96/40140, assigned to GuilfordPharmaceuticals, Inc., published Dec. 19, 1996; Hamilton et al., WO96/40633, assigned to Guilford Pharmaceuticals, Inc., published Dec. 19,1996; Steiner et al., U.S. Pat. No. 5,696,135, assigned to GPI NILHoldings, Inc., issued Dec. 9, 1997; Hamilton et al., U.S. Pat. No.5,614,547, assigned to Guilford Pharmaceuticals, Inc., issued Mar. 25,1997; Steiner et al., WO 97/16190, assigned to Guilford Pharmaceuticals,Inc., published May 9, 1997; Zelle et al., WO 96/36630, assigned toVertex Pharmaceuticals, Inc., published Nov. 21, 1996; Armistead et al.,WO 97/36869, assigned to Vertex Pharmaceuticals, Inc., published Oct. 9,1997; Zelle et al., WO 96/15101, assigned to Vertex Pharmaceuticals,Inc., published May 23, 1996; Armistead et al., WO 92/19593, assigned toVertex Pharmaceuticals, Inc., published Nov. 12, 1992; Armistead et al.,WO 94/07858, assigned to Vertex Pharmaceuticals, Inc., published Apr.14, 1994; Zelle et al., WO 95/26337, assigned to Vertex Pharmaceuticals,Inc., published Oct. 5, 1995; Duffy et al., WO 92/21313, assigned toVertex Pharmaceuticals, Inc., published Dec. 10, 1992; Armistead et al.,U.S. Pat. No. 5,192,773, assigned to Vertex Pharmaceuticals, Inc.,issued Mar. 9, 1993; Armistead et al., U.S. Pat. No. 5,330,993, assignedto Vertex Pharmaceuticals, Inc., issued Jul. 19, 1994; Armistead et al.,U.S. Pat. No. 5,622,970, assigned to Vertex Pharmaceuticals, Inc.,issued Apr. 22, 1997; Armistead et al., U.S. Pat. No. 5,654,332,assigned to Vertex Pharmaceuticals, Inc., issued Aug. 5, 1997; Armisteadet al., U.S. Pat. No. 5,620,971, assigned to Vertex Pharmaceuticals,Inc., issued Apr. 15, 1997; Zelle et al., U.S. Pat. No. 5,543,423,assigned to Vertex Pharmaceuticals, Inc., issued Aug. 6, 1996; Armisteadet al., U.S. Pat. No. 5,516,797, assigned to Vertex Pharmaceuticals,Inc., issued May 14, 1996; Armistead et al., U.S. Pat. No. 5,665,774,assigned to Vertex Pharmaceuticals, Inc., issued Sep. 9, 1997; Andres etal., “Conformationally Defined Analogs of Prolylamides. trans-ProlylPeptidomimetics”, Journal of Organic Chemistry, Vol. 58, pp. 6609-6613(1993); and Armistead et al., “Design, Synthesis and Structure ofNon-macrocyclic Inhibitors of FKBP12, the Major Binding Protein for theImmunosuppressant FK506”, Acta Crystallographica, D51, pp. 522-528(1995).

Surprisingly, the present inventors have discovered a novel class ofcompounds which arrest and/or reverse hair loss or promote hair growthbut do not share the complex, macrocyclic structure of FK506. Thepresent inventors have further discovered compounds among this novelclass which invoke hair growth yet are surprisinglynon-immunosuppressive or are nominally immunosuppressive. The minimizedand/or absent immunosuppressive activity of these hypertrichoticcompounds are distinct advantages as compared to the immunosuppressivecompounds cyclosporin A and FK506.

SUMMARY OF THE INVENTION

The present invention relates to compounds and compositions which areparticularly useful for treating hair loss in mammals, includingarresting and/or reversing hair loss and promoting hair growth. Thepresent compounds and compositions may also be useful against a varietyof disorders including, for example, multi-drug resistance, humanimmunodeficiency virus (HIV), cardiac injury, and neurologicaldisorders, and are useful for controlling parasites and invokingimmunosuppression. The compounds of the present invention have thestructure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzableamides, esters, and imides thereof, wherein the moieties Z, Q, W, X, Y,V, A, G, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions which areparticularly useful for treating hair loss in mammals, includingarresting and/or reversing hair loss and promoting hair growth.

In addition to discovering that the present compounds are useful fortreating hair loss, the present inventors have also surprisinglydiscovered that immunosuppression is not required for hair growthstimulation. The present inventors have further discovered compoundsthat are useful for treating hair loss but are surprisinglynon-immunosuppressive. Preferred compounds of the present invention aretherefore, as defined herein, non-immunosuppressive. The presentcompounds are also useful for treating a variety of other conditions asdescribed herein below.

Publications and patents are referred to throughout this disclosure. Allreferences cited herein are hereby incorporated by reference.

All percentages, ratios, and proportions used herein are by weightunless otherwise specified.

Definition and Usage of Terms

The following is a list of definitions for terms used herein:

As used herein “salt” is a cationic salt formed at any acidic (e.g.,carboxyl) group, or an anionic salt formed at any basic (e.g., amino)group. Many such salts are known in the art. Preferred cationic saltsinclude the alkali metal salts (such as, for example, sodium andpotassium), alkaline earth metal salts (such as, for example, magnesiumand calcium), and organic salts. Preferred anionic salts include thehalides (such as, for example, chloride salts). Such acceptable saltsmust, when administered, be appropriate for mammalian use.

As used herein unless otherwise specified, “alkenyl” is an unsubstitutedor substituted, straight or branched hydrocarbon chain radical havingfrom 2 to about 15 carbon atoms; preferably from 2 to about 10 carbonatoms; more preferably from 2 to about 8 carbon atoms, and mostpreferably from about 2 to about 6 carbon atoms. Alkenyls have at leastone olefinic double bond. Non-limiting examples of alkenyls includevinyl, allyl, and butenyl.

As used herein unless otherwise specified, “alkoxy” is an oxygen radicalhaving an alkyl, alkenyl, or alkynyl, preferably an alkyl or alkenyl,and most preferably an alkyl substituent. Examples of alkoxy radicalsinclude —O-alkyl and —O-alkenyl. An alkoxy radical may be substituted orunsubstituted.

As used herein unless otherwise specified, “aryloxy” is an oxygenradical having an aryl substituent. An aryloxy radical may besubstituted or unsubstituted.

As used herein unless otherwise specified, “alkyl” is an unsubstitutedor substituted, straight or branched saturated hydrocarbon chain radicalhaving from 1 to about 15 carbon atoms; preferably from 1 to about 10carbon atoms; more preferably from 1 to about 6 carbon atoms; and mostpreferably from 1 to about 4 carbon atoms. Preferred alkyls include, forexample, methyl, ethyl, propyl, iso-propyl, and butyl.

As used herein, “alkylene” refers to an alkyl, alkenyl, or alkynyl whichis a diradical. For example, “methylene” is —CH₂—. Alkylenes may besubstituted or unsubstituted.

As used herein unless otherwise specified, “aryl” is an aromatic ringradical which is either carbocyclic or heterocyclic. Preferred arylgroups include, for example, phenyl, benzyl, tolyl, xylyl, cumenyl,napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl,thiazolyl, pyrimidinyl, quinolinyl, triazolyl, tetrazolyl,benzothiazolyl, benzofuryl, indolyl, indenyl, azulenyl, fluorenyl,anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl,oxadiazolyl, indolizinyl, indolyl, isoindolyl, purinyl, quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, and the like. Aryls may besubstituted or unsubstituted.

As used herein unless otherwise specified, “arylalkenyl” is an alkenylradical substituted with an aryl group or an aryl radical substitutedwith an alkenyl group. Arylalkenyls may be substituted or unsubstituted.

As used herein unless otherwise specified, “arylalkyl” is an alkylradical substituted with an aryl group or an aryl radical substitutedwith an alkyl group. Preferred arylalkyl groups include benzyl,phenylethyl, and phenylpropyl. Arylalkyls may be substituted orunsubstituted.

As used herein, “biohydrolyzable amides” are amides of the compounds ofthe present invention which do not interfere with the activity of thecompound, or that are readily converted in vivo by a mammalian subjectto yield an active compound.

As used herein, “biohydrolyzable esters” are esters of the compounds ofthe present invention which do not interfere with the activity of thecompound, or that are readily converted in vivo by a mammalian subjectto yield an active compound.

As used herein, “biohydrolyzable imides” are imides of the compounds ofthe present invention which do not interfere with the activity of thecompound, or that are readily converted in vivo by a mammalian subjectto yield an active compound.

As used herein unless otherwise specified, “carbocyclic ring”,“carbocycle”, or the like is a hydrocarbon ring radical. Carbocyclicrings are monocyclic or are fused, bridged, or spiro polycyclic rings.Unless otherwise specified, monocyclic rings contain from 3 to about 9atoms, preferably from about 4 to about 7 atoms, and most preferably 5or 6 atoms. Polycyclic rings contain from about 7 to about 17 atoms,preferably from about 7 to about 14 atoms, and most preferably 9 or 10atoms. Carbocyclic rings (carbocycles) may be substituted orunsubstituted.

As used herein unless otherwise specified, “cycloalkyl” is a saturatedcarbocyclic or heterocyclic ring radical. Preferred cycloalkyl groupsinclude, for example, cyclobutyl, cyclopentyl, and cyclohexyl.Cycloalkyls may be substituted or unsubstituted.

As used herein unless otherwise specified, “halo”, “halogen”, “halide”,or the like means a chloro, bromo, fluoro, or iodo atom radical,preferably bromo, chloro, or fluoro, more preferably chloro or fluoro.

As used herein unless otherwise specified, “heteroalkenyl” is an alkenylradical containing carbon atoms and one or more heteroatoms within thealkenyl chain (e.g., —CHOCH₂ rather than pendant from like, e.g., C(O))wherein the heteroatoms are selected from oxygen, sulfur, nitrogen, andphosphorous, more preferably, oxygen, sulfur, and nitrogen.Heteroalkenyls may be substituted or unsubstituted.

As used herein unless otherwise specified, “heteroalkyl” is an alkylradical containing carbon atoms and one or more heteroatoms within thealkyl chain (e.g., —CH₂OCH₂ rather than pendant from like, e.g., C(O))wherein the heteroatoms are selected from the group consisting ofoxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen,sulfur, and nitrogen. Heteroalkyls may be substituted or unsubstituted.

As used herein unless otherwise specified, “heteroaryl” is an arylradical containing carbon atoms and one or more heteroatoms within thearyl ring (e.g., —CHOCH—) rather than pendant from like, e.g., C(O))wherein the heteroatoms are selected from the group consisting ofoxygen, sulfur, nitrogen, and phosphorous, more preferably, oxygen,sulfur, and nitrogen. Heteroaryls may be substituted or unsubstituted.

As used herein unless otherwise specified, “heteroarylalkenyl” is anarylalkenyl radical wherein the aryl group is a heteroaryl and/or thealkenyl group is a heteroalkenyl. Heteroarylalkenyls may be substitutedor unsubstituted.

As used herein unless otherwise specified, “heteroarylalkyl” is anarylalkyl radical wherein the aryl group is a heteroaryl and/or thealkyl group is a heteroalkyl. Heteroarylalkyls may be substituted orunsubstituted.

As used herein unless otherwise specified, “heterocyclic ring”,“heterocycle”, or the like is a ring radical comprised of carbon atomsand one or more heteroatoms in the ring wherein the heteroatoms areselected from the group consisting of oxygen, sulfur, nitrogen, andphosphorous, more preferably, oxygen, sulfur, and nitrogen. Heterocyclesare monocyclic or are fused, bridged, or spiro polycyclic rings. Unlessotherwise specified, monocycles contain from 3 to about 9 atoms,preferably from about 4 to about 7 atoms, and most preferably 5 or 6atoms. Polycycles contain from about 7 to about 17 atoms, preferablyfrom about 7 to about 14 atoms, and most preferably 9 or 10 atoms.Heterocyclic rings (heterocycles) may be substituted or unsubstituted.

As used herein unless otherwise specified, “heterocycloalkyl” is asaturated heterocycle. Heterocycloalkyls may be substituted orunsubstituted.

As used herein unless otherwise specified, a “lower” moiety (e.g.,“lower” alkyl) is moiety having 1 to about 6, preferably 1 to about 4,carbon atoms.

As used herein, “pharmaceutically acceptable” means suitable for use ina human or other mammal.

As used herein, “safe and effective amount of a compound” (orcomposition, or the like) means an amount that is effective to exhibitbiological activity, preferably wherein the biological activity isarresting and/or reversing hair loss or promoting hair growth, at thesite(s) of activity in a mammalian subject, without undue adverse sideeffects (such as toxicity, irritation, or allergic response),commensurate with a reasonable benefit/risk ratio when used in themanner of this invention.

As used herein, a “spiro moiety” is a cyclic moiety sharing a carbon onanother ring, preferably the Z ring. Such spiro moiety may becarbocyclic or heterocyclic. Spiro moieties may be substituted orunsubstituted.

As used herein unless otherwise specified, the term “substituted” inreference to a group, moiety, or the like, means having one or moresubstituent groups each independently selected from hydrogen, alkoxy,hydroxy, nitro, amino, alkylamino, cyano, halo, carboxy, thiol, imino,and aryloxy (with additional allowed substituents on the G moiety whichare selected from oxo, amido, —O-alkyl-C(O)OR₃₂, and —O-alkyl-C(O)NHR₃₂,wherein R₃₂ is selected from hydrogen and alkyl) preferably hydrogen,alkoxy, aryloxy, hydroxy, nitro, amino, halo, and thiol, more preferablyhydrogen, alkoxy, hydroxy, nitro, amino, alkylamino, and halo, even morepreferably hydrogen, halo, hydroxy, and alkoxy, and most preferablyhydrogen.

As used herein unless otherwise specified, the term “unsubstituted”means substitution by a hydrogen moiety. However, a group mayalternatively be consistently described as being “substituted” whereinthe substitution is with a hydrogen moiety.

As used herein, wherein any variable, moiety, group, or the like occursmore than one time in any variable or structure, its definition at eachoccurrence is independent of its definition at every other occurrence.

Compounds of the Present Invention

The compounds of the present invention have the structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzableamides, esters, and imides thereof, wherein:

(a) V is a heteroatom wherein the heteroatom is nitrogen;

(b) G is selected from alkyl having at least 3 carbon atoms, alkenyl,heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(c) Z is a saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-memberedheterocycle optionally containing one or more additional heteroatomsselected from O, N, S, S(O), S(O)₂, and P((O)OK);

(d) K is selected from hydrogen, alkyl, alkenyl, heteroalkyl,heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroarylalkyl, arylalkenyl, and heteroarylalkenyl;

(e) W is selected from nil, hydrogen and lower alkyl;

(f) A is selected from nil and alkyl;

(g) X and Y are each, independently, selected from C(O), N, O, and S,wherein:

(i) when X is C(O) then R₃ is nil and Y is selected from N, O, and S;

(ii) when X is N then R₃ is selected from hydrogen, alkyl, andarylalkyl, Y is C(O), and R₂ is nil;

(iii) when X is O then R₃ is nil, Y is C(O), and R₂ is nil; and

(iv) when X is S then R₃ is nil, Y is C(O), and R₂ is nil;

(h) R₂ and R₃ are each, independently, selected from nil, hydrogen,alkyl, and arylalkyl;

(i) R₄ is alkyl;

(j) R₅ and R₆ are each, independently, selected from nil, hydrogen,alkyl having at least three carbon atoms, alkenyl, heteroalkyl,heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroarytalkyl, arylalkenyl, and heteroarylalkenyl; or wherein R₅ andR₆ are bonded together to form a carbocyclic or hetercyclic ring;wherein at least one of R₅ or R6 is not nil or hydrogen;

(k) Q is selected from CH₂, CHR₇, NR₇, S, S(O), and S(O)₂;

(l) R₇, R₈, and R₉, and R₁₀ are each, independently, selected from nil,hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl,heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino, —R₁₄SR₁₅,—R₁₄S(O₂)R₁₅, —R₁₄S(O)R₁₅, —R₁₄C(O)R₁₅, —R₁₄C(O)NR₁₅R₁₆, —R₁₄C(O)OR₁₅,—R₁₄OR₁₅, —R₁₄NR₁₅R₁₆, —R₁₄P(O)NR₁₅R₁₆, —R₁₄P(O)OR₁₅R₁₆, and a spiromoiety, and wherein R₇ and R₈ may be optionally bonded together to forman aromatic or saturated, carbocyclic or heterocyclic ring wherein thering is fused to Z; wherein when A is nil and X is C(O) at least one ofR₇, R₈, R₉, and R₁₀ is not nil or hydrogen;

(m) R₁₄, and R₁₅ are each, independently, selected from nil, hydrogen,alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, andheteroarylalkenyl; and

(n) R₁₆ is selected from hydrogen and alkyl.

The Ring System Z

The present compounds are comprised of a ring system, Z, which is asaturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycle.Preferably the Z ring system is a 5-, 6-, or 7-membered heterocycle,more preferably a 5- or 6-membered heterocycle.

At the 1-position of the ring system is the V heteroatom which is anitrogen atom. The Z ring optionally contains one or more heteroatoms orheteromoieties (herein collectively described as heteroatoms forsimplicity) in addition to the V nitrogen wherein the additionalheteroatoms are selected from oxygen (O), nitrogen (N), sulfur (S),sulfoxide (S(O)), sulfone (S(O)₂), and phosphonate (P((O)OK)).Preferably the additional heteroatoms are selected from the groupconsisting of O, N, S, S(O), and S(O)₂, but more preferably Z does notcontain any heteroatoms other than the V nitrogen at the 1-position. Atthe 3-position of the ring system is the Q moiety which is from CH₂,CHR₇, NR₇, S, S(O), and S(O)₂, preferably CH₂, CHR₇, NR₇, and morepreferably CH₂ and CHR₇. Most preferably, the Q moiety is CH₂.

Of course, wherein N is an additional heteroatom and also wherein Q isN, the additional N heteroatom and/or Q must be substituted, mostpreferably with hydrogen or alkyl. The S(O), S(O)₂, and P(O)OKheteroatoms are depicted below in Table 1 for clarity:

TABLE 1 S(O)

S(O)₂

P(O)OK

The G Moiety

The G moiety is attached to the —SO₂— moiety and is selected from alkylhaving at least 3 carbon atoms, alkenyl, heteroalkyl, heteroalkenyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl,arylalkenyl, and heteroarylalkenyl. The G moiety is preferablysubstituted with at least one substituent other than hydrogen. Inaddition to the substituents defined herein which can substitute allmoieties, the substituents oxo, amido, —O-alkyl-C(O)OR₃₂, and—O-alkyl-C(O)NHR₃₂, wherein R₃₂ is selected from hydrogen and alkyl, mayalso substitute on the G moiety.

The G moiety is preferably selected from alkyl having at least 3 carbonatoms, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, andheteroarylalkyl, even more preferably aryl, arylalkyl, andheteroarylalkyl, most preferably aryl. The most preferred aryl for the Gmoiety is substituted aryl (most preferably substituted phenyl),particularly aryl having at least one alkoxy substituent. Particularlypreferred G moieties are shown below in Table 2.

TABLE 2 Preferred G Moieties

The A—X—Y—R₄ Moiety

At the 2-position of the Z ring is the A—X—Y—R₄ moiety which issubstituted, as described herein, by R₂, R₃, R₅, and R₆.

The A moiety of the side chain is selected from nil and alkyl. However,wherein A is nil and X is C(O), at least one of the ring substituentsR₇, R₈, R₉, and R₁₀ (each of which are described more fully hereinbelow) is not nil or hydrogen. Most preferably, the A moiety is nil,meaning that most preferably, at least one of R₇, R₈, R₉, and R₁₀ is notnil or hydrogen. Of course, wherein A is nil, X is directly attached tothe Z ring.

The X moiety of the side chain is dependent upon the structure of the Ymoiety and vice versa. X and Y are each, independently, selected fromC(O) (i.e., carbonyl), N, O, S, with the following limitations:

(i) when X is C(O) then R₃ is nil and Y is selected from N, O, and S;

(ii) when X is N then R₃ is selected from hydrogen, alkyl, andarylalkyl, Y is C(O), and R₂ is nil;

(iii) when X is O then R₃ is nil, Y is C(O), and R₂ is nil; and

(iv) when X is S then R₃ is nil, Y is C(O), and R₂ is nil;

Preferably, X and Y are each, independently, selected from C(O), N, andO. More preferably, X and Y are each, independently, selected from isC(O) and N.

X and Y are substituted by R₃ and R₂, respectively. R₃ and R₂ are each,independently, selected from nil, hydrogen, alkyl, and arylalkyl.Wherein X is O or S, then R₃ is nil, and wherein Y is O or S, then R₂ isnil. Wherein X is N, then R₃ is selected from hydrogen, alkyl, andarylalkyl, preferably hydrogen and alkyl, most preferably hydrogen.Wherein Y is N, then R₂ is selected from hydrogen, alkyl, and arylalkyl,preferably hydrogen and alkyl, most preferably hydrogen.

The R₄ moiety is an alkyl moiety. The preferred alkyl moieties followthe preferred limitations set forth above, with the most preferred R₄moiety being a methylene or methyne group (i.e., a C₁ moiety bearingonly one hydrogen substituent).

The R₅ and R₆ moieties are each directly attached to R₄. R₅ and R₆ areeach, independently, selected from nil, hydrogen, alkyl having at leastthree carbon atoms, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, andheteroarylalkenyl; or wherein R₅ and R₆ are bonded together to form acarbocyclic or hetercyclic ring; wherein at least one of R₅ or R₆ is notnil or hydrogen.

Preferably, R₅ and R₆ are each, independently, selected from nil,hydrogen, alkyl having at least three carbon atoms, alkenyl,heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; whereinat least one of R₅ or R₆ is not nil or hydrogen. More preferably, R₅ andR₆ are each, independently, selected from alkyl having at least threecarbon atoms, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, and heteroarylalkyl. Most preferably, R₅ and R₆ are each,independently, arylalkyl. It is often preferred that R₅ and R₆ areequivalent moieties. Of course, R₅ and R₆ may be each, independently,substituted. Exemplary R₅ and R₆ moieties are shown in Table 3 below.

TABLE 3 Exemplary R₅ and R₆ Moieties

The W Moiety

The Z ring may be substituted at the 2-position by an additional moiety,W. The W moiety is selected from nil, hydrogen, and lower alkyl,preferably hydrogen and lower alkyl, most preferably hydrogen. Wherein Wis lower alkyl, W is most preferably methyl.

The Z Ring Substituents R₇, R₈, R₉ and R₁₀

In addition to the aforementioned substituents at positions 1 and 2 ofthe Z ring, the Z ring may also have additional substituents at theother available positions, such additional substituents being defined asR₇, R₈, R₉, and R₁₀. These substituents R₇, R₈, and R₉, and R₁₀ areeach, independently, selected from nil, hydrogen, alkyl, alkenyl,heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, halo, cyano,hydroxy, oxo, imino, —R₁₄SR₁₅, —R₁₄S(O₂)R₁₅, —R₁₄S(O)R₁₅—R₁₄C(O)R₁₅,—R₁₄C(O)NR₁₅R₁₆, —R₁₄C(O)OR₁₅, —R₁₄OR₁₅, —R₁₄NR₁₅R₁₆, —R₁₄P(O)NR₁₅R₁₆,—R₁₄P(O)OR₁₅R₁₆, and a spiro moiety, and wherein R₇ and R₈ may beoptionally bonded together to form an aromatic or saturated, carbocyclicor heterocyclic ring wherein the ring is fused to Z; wherein when A isnil and X is C(O) at least one of R₇, R₈, R₉, and R₁₀ is not nil orhydrogen. R₁₄, and R₁₅ are each, independently, selected from nil,hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, andheteroarylalkenyl. R₁₆ is selected from hydrogen and alkyl.

Preferably, R₇, R₈, and R₉, and R₁₀ are each, independently, selectedfrom nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, halo, hydroxy, oxo,—R₁₄SR₁₅, —R₁₄S(O₂)R₁₅, —R₁₄S(O)R₁₅, —R₁₄C(O)R₁₅, —R₁₄C(O)NR₁₅R₁₆,—R₁₄OR₁₅, —R₁₄NR₁₅R₁₆, and a spiro moiety, and wherein R₇ and R₈ may beoptionally bonded together to form an aromatic or saturated, carbocyclicor heterocyclic second ring wherein the second ring is fused to Z. Morepreferably, R₇, R₈, and R₉, and R₁₀ are each, independently, selectedfrom nil, hydrogen, alkyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl,heteroarylalkyl, halo, hydroxy, oxo, —R₁₄SR₁₅, —R₁₄S(O₂)R₁₅,—R₁₄S(O)R₁₅, —R₁₄C(O)R₁₅, —R₁₄C(O)NR₁₅R₁₆, —R₁₄OR₁₅, —R₁₄NR₁₅R₁₆, and aspiro moiety, and wherein R₇ and R₈ may be optionally bonded together toform an aromatic or saturated, carbocyclic or heterocyclic second ringwherein the second ring is fused to Z. Even more preferably, R₇, R₈, andR₉, and R₁₀ are each, independently, selected from nil, hydrogen, alkyl,heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroarylalkyl, halo,hydroxy, —R₁₄C(O)R₁₅, —R₁₄C(O)NR₁₅R₁₆, —R₁₄OR₁₅, —R₁₄NR₁₅R₁₆, and aspiro moiety, and wherein R₇ and R₈ may be optionally bonded together toform an aromatic or saturated, carbocyclic or heterocyclic second ringwherein the second ring is fused to Z. Most preferably, R₇ and R₈ arebonded together to form an aromatic or saturated (preferably aromatic),carbocyclic or heterocyclic (preferably carbocyclic) second ring whereinthe second ring is fused to Z.

Wherein R₇ and R₈ are bonded together to form an aromatic or saturated,carbocyclic or heterocyclic second ring wherein the second ring is fusedto Z, the second ring may, of course, be substituted or unsubstituted. Apreferred second ring is phenyl.

Preferably, at least one of R₇, R₈, R₉, and R₁₀ is not nil or hydrogen.

Exemplary compounds of the present invention are presented in thefollowing tables.

TABLE 4 Exemplary Compounds of the Present Invention

and

wherein in Table 4, R₃₅ is selected from hydrogen and —OR₃₆, wherein R₃₆is selected from hydrogen and alkyl.

TABLE 5 Exemplary Compounds of the Present Invention

wherein, in Table 5, R₁₈, R₁₉, and R₂₀ are each, indenpendently,selected from hydrogen, alkoxy, aryloxy, hydroxy, nitro, amino, halo,and thiol.

TABLE 6 Exemplary Compounds of the Present Invention

wherein in Table 6, R₃₀ is selected from —OR₃₂ and —OCH₂C(O)OR₃₂,wherein R₃₂ is selected from hydrogen and alkyl, and wherein R₃₅ isselected from hydrogen and —OR₃₆, wherein R₃₆ is selected from hydrogenand alkyl.

TABLE 7 Exemplary Compounds of the Present Invention

wherein in Table 7, R₃₅ is selected from hydrogen and —OR₃₆, wherein R₃₆is selected from hydrogen and alkyl.

TABLE 8 Exemplary Compounds of the Present Invention

wherein in Table 8, R₃₀ and R₃₅ are each, independently, selected from—OR₃₂ and —OCH₂C(O)OR₃₂, wherein R₃₂ is selected from hydrogen andalkyl.

Analytical Methods

The present compounds are hair growth actives, the more preferred amongthese being non-immunosuppressive. The compounds (test compounds) of thepresent invention may be tested for their ability to induce anagen andtheir immunosuppressive activity (or lack thereof) using the followingmethods. Alternatively, other methods well-known in the art may be used(but with the term “non-immunosuppressive” being defined according tothe method disclosed herein).

Telogen Conversion Assay

The Telogen Conversion Assay measures the potential of a test compoundto convert mice in the resting stage of the hair growth cycle(“telogen”), to the growth stage of the hair growth cycle (“anagen”).

Without intending to be limited by theory, there are three principalphases of the hair growth cycle: anagen, catagen, and telogen. It isbelieved that there is a longer telogen period in C3H mice (HarlanSprague Dawley, Inc., Indianapolis, Ind.) from approximately 40 days ofage until about 75 days of age, when hair growth is synchronized. It isbelieved that after 75 days of age, hair growth is no longersynchronized. Wherein about 40 day-old mice with dark fur (brown orblack) are used in hair growth experiments, melanogenesis occurs alongwith hair (fur) growth wherein the topical application of hair growthpromoters are evaluated. The Telogen Conversion Assay herein below isused to screen compounds for potential hair growth by measuringmelanogenesis.

Three groups of 44 day-old C3H mice are utilized: a vehicle controlgroup, a positive control group, and a test compound group, wherein thetest compound group is administered a compound of the present invention.The length of the assay is at least 19 days with 15 treatment days(wherein the treatment days occur Mondays through Fridays). Day 1 is thefirst day of treatment. Most studies will end on Day 19, but a few maybe carried out to Day 24 if the melanogenesis response looks positive,but occurs slowly. A typical study design is shown in Table 9 below:

TABLE 9 Group Animal Com- Application Length of # # pound Concentrationvolume Study 1 1-10 Test 5% in 400 μL topical 19 or 24 Com- vehicle**days pound 2 11-20 Cyclo- 0.19% in 400 μL topical 19 or 24 sporinvehicle** days A 3 21-30 Vehi- N/A 400 μL topical 19 or 24 cle** days**The vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethylisosorbide (commercially available from Sigma Chemical Co., St. Louis,MO).

The mice are treated topically Monday through Friday on their lower back(base of tail to the lower rib). A pipettor and tip are used to deliver400 μL to each mouse's back. The 400 μL application is applied slowlywhile moving hair on the mouse to allow the application to reach theskin.

While each treatment is being applied to the mouse topically, a visualgrade of from 0 to 4 will be given to the skin color in the applicationarea of each animal. As the mice convert from telogen to anagen theirskin color will become more bluish-black. As indicated in Table 10, thegrades 0 to 4 represent the following visual observations as the skinprogresses from white to bluish-black:

TABLE 10 Visual Observation Grade Whitish Skin Color 0 Skin is lightgray (indication of initiation of anagen) 1 Appearance of Blue Spots 2Blue Spots are aggregating to form one large blue area 3 Skin is darkblue (almost black) with color covering majority of 4 treatment area(indication of mouse in full anagen)

Immunosuppression Assay

The immunosuppression assay herein predicts the immunosuppressiveactivity of a compound of the present invention. The assay is performedas follows:

Spleens are excised from euthanized (CO₂ asphyxiation) adult male C3Hmice ranging in age from seven to sixteen weeks old (live micecommercially available from Harlan Sprague Dawley, Inc., Indianapolis,Ind.). The spleens are placed immediately in cold Hanks Balanced SaltSolution (HBSS, commercially available from Gibco-BRL, Gaithersburg,Md.). The spleens are then ground up between frosted glass slides andfiltered through a sterile screen to remove tissue debris. The resultingcell suspension is underlayed with an equal volume of Ficoll-Paque Plus(commercially available from Pharmacia Biotech, Piscataway, N.J.) andcentrifuged at 400× g for approximately forty minutes at 20° C. in orderto collect the splenocytes. The splenocytes are collected from theinterface using a disposable pipet and are washed twice with HBSS,followed by centrifugation at 100× g for ten min at 20° C. Splenocytesare resuspended in five to ten mL of cell culture media consisting ofphenol red-free RPMI 1640 (culture media commercially available fromGibco-BRL) containing 10% heat-inactivated fetal bovine serum(Gibco-BRL), penicillin (50 U/mL), streptomycin (100 μ/mL), L-glutamine(2 mM), 2-mercaptoethanol (10⁻⁵ M), andN-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) (10 mM). Thecells are counted and checked for viability using, for example, trypanblue. Splenocytes are resuspended in medium at 10⁶ cells/mL and pipettedinto 96 well round bottom plates at 10⁵ cells/well. Splenocytes areactivated by addition of 50 μL/well of conconavalin A (final assayconcentration=5 μg/ml) in the presence or absence of a test compound.Test compounds are made up as stock solutions in methyl sulfoxide(DMSO), then diluted in medium and 50 μL/well added, such that the finalconcentration of DMSO in the assay is below 0.05%. The plates areincubated at 37° C. with 5% CO₂ for 48 hours. After 48 hours, the cellsare pulsed with 1 μCi/well of methyl-³H-thymidine (commerciallyavailable from Amersham, Buckinghamshire, England) and incubated anadditional 24 hours.

After 24 hours, the cells are harvested onto GF/C filter plates(commercially available from Packard, Downers Grove, Ill.), solubilizedin Microscint 20 (Packard), and counted on a TopCount microplatescintillation and luminescence plate counter (Packard). Activity ismeasured as a percentage of control activity in the absence of testcompound and plotted versus test compound concentration. The data arefit to a 4-parameter curve fit (Sigmaplot) and IC₅₀ values arecalculated. As used herein, test compounds are considerednon-immunosuppressive if, by using this method, the ratio of(cyclosporin A IC₅₀/test compound IC₅₀)×100 is less than or equal to0.02, i.e., a non-immunosuppressive test compound has ≦2% of theimmunosuppressive activity of cyclosporin A.

Cell viability is assessed using the MTT(3-[4,5-dimethyl-thiazoyl-2-yl]2,5-diphenyl-tetrazolium bromide) dyeassay as described by Nelson et al., Journal of Immunology, Vol. 150,No. 6, pp. 2139-2147 (1993), with the exception that the assay iscarried out in serum-free, phenol red-free RPMI 1640 and the dye issolubilized in 100 μL/well DMSO and read at an OD of 540 nm with abackground correction at 650 nm on a SpectraMax Plus microplate reader(Molecular Devices, Menlo Park, Calif.).

Multi-Drug Resistance

As disclosed herein, the present compounds are also useful, for example,to increase the antiproliferative activity of a drug and/or preventand/or treat multi-drug resistance. The present compounds may be assayedfor this property as described in U.S. Pat. No. 5,744,485, Zelle et al.,assigned to Vertex Pharmaceuticals Inc., issued Apr. 28, 1998, U.S. Pat.No. 5,726,184, Zelle et al., assigned to Vertex Pharmaceuticals Inc.,issued Mar. 10, 1998, U.S. Pat. No. 5,620,971, Armistead et al.,assigned to Vertex Pharmaceuticals Inc., issued Apr. 15, 1997, and U.S.Pat. No. 5,543,423, Zelle et al., assigned to Vertex PharmaceuticalsInc., issued Aug. 6, 1996.

Methods of Making

The compounds of the present invention are prepared according to methodswhich are well-known to those skilled in the art. The starting materialsused in preparing the compounds of the invention are known, made byknown methods, or are commercially available as a starting material.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction. Examples of such manipulations arediscussed in standard texts such as J. March, Advanced OrganicChemistry, John Wiley & Sons, 1992.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionalities are masked or protected inthe compound, thus increasing the yield of the reaction and/or avoidingany undesirable side reactions. Often, the skilled artisan utilizesprotecting groups to accomplish such increased yields or to avoid theundesired reactions. These reactions are found in the literature and arealso well within the scope of the skilled artisan. Examples of many suchmanipulations can be found in, for example, T. Greene, Protecting Groupsin Organic Synthesis, John Wiley & Sons, 1981.

The compounds of the present invention may have one or more chiralcenter. As a result, one may selectively prepare one optical isomer,including diastereomers and enantiomers, over another, for example bychiral starting materials, catalysts or solvents, or may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers may beseparated using known methods, such as through the use of, for example,chiral salts and chiral chromatography.

In addition, it is recognized that one optical isomer, including adiastereomer and enantiomer, or a stereoisomer, may have favorableproperties over the other. Thus, when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastereomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

The following provides non-limiting examples illustrating morespecifically the methods of making various compounds of the presentinvention.

As used herein, the following abbreviations are used:

Reagent Abbreviation N,N-dimethylformamide DMF 1-hydroxybenzotriazolehydrate HOBt tert-butoxycarbonyl BOC(benzotriazol-1-yloxy)tripyrrolidinophosphonium PyBOPhexafluorophosphate (commercially available from Fluka Chemical,Switzerland) tetrahydrofuran THF1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDAC trimethylsilyltrifluoromethanesulfonate TMS-OTf N,N-diisopropylethylamine i-Pr₂NEt ori-Pr₂EtN trifluoroacetic acid TFA lithium hydroxide LiOH

EXAMPLE 1

1a. (S)-(N-tert-Butoxycarbonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid 1,7-diphenyl-4-heptylamide

(S)-(N-tert-Butoxycarbonyl)-1,2,3,4-tetrahydro-3-isoquinoline carboxylicacid (4.90 g, 17.7 mmol) is dissolved in 160 mL of DMF.1,7-Diphenyl-4-aminoheptane (4.30 g, 16.1 mmol) andN,N-diisopropylethylamine (4.16 g, 32.2 mmol) are added followed byPyBOP (8.80 g, 16.9 mmol). The reaction is stirred for 18.5 hours atroom temperature, then poured onto ice-cold 0.1N HCl (600 mL) andextracted with ethyl acetate (600 mL). The organic layer is washedsuccessively with brine (100 mL), saturated NaHCO₃ solution (300 mL),and brine (2×200 mL). The organic solution is dried over MgSO₄,filtered, and concentrated under reduced pressure. Purification of theproduct by chromatography on silica gel (8:2 hexane:ethyl acetate)affords the desired amide 1a.

1b. (S)-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid1,7-diphenyl-4-heptylamide

The amide 1a (8.07 g, 15.3 mmol) is dissolved in 150 mL of anhydrousdichloromethane. Trifluoroacetic acid (120 mL) is added dropwise over afive minute period. After 2 hours the mixture is cooled in an ice-bathand saturated K₂CO₃ solution is added until the pH is approximately 8.The mixture is transferred to a separatory funnel containingdichloromethane (200 mL) and water (200 mL) and shaken. The organiclayer is washed with water (200 mL) before drying over MgSO₄. Themixture is filtered and concentrated under reduced pressure to affordthe desired amine 1b.

1c.(S)-N-(3′,4′-Dimethoxyphenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid 1,7-diphenyl-4-heptylamide

The amide 1b (5.0 g, 11.7 mmol) is dissolved in anhydrous methylenechloride (100 mL) at room temperature. N,N-diisopropylethylamine (2.55mL, 14.7 mmol) is added and the solution is cooled to 5° C.3′,4′-Dimethoxyphenylsulfonyl chloride (3.47 g, 14.7 mmol) is added inone portion. The reaction mixture is stirred for 18 hours at roomtemperature then concentrated to one-half volume. The concentrate ispoured onto ethyl acetate (300 mL) and washed successively with 0.1M HCl(100 mL), saturated sodium bicarbonate solution (100 mL), and brine (50mL). The organic solution is dried over MgSO₄, filtered, andconcentrated in vacuo. Purification of the crude product by preparativechromatography (silica gel; gradient elution with 4:1 to 1:1hexane:ethyl acetate) affords the desired sulfonamide 1c.

EXAMPLE 2

2a (N-tert-Butoxycarbonyl)-4(R)-benzyloxpyrrolidine-2(S)-carboxylic acid1,7-diphenyl-4-heptylamide

(N-tert-Butoxycarbonyl)-4(R)-benzyloxypyrrolidine-2(S)-carboxylic acid(5.68 g, 17.7 mmol) is dissolved in 160 mL of DMF.1,7-Diphenyl-4-aminoheptane (4.30 g. 16.1 mmol) andN,N-diisopropylethylamine (4.16 g, 32.2 mmol) are added followed byPyBOP (9.20 g, 17.1 mmol). The reaction is stirred for 20.5 hours atroom temperature, then poured onto ice-cold 0.1N HCl (600 mL) andextracted with ethyl acetate (600 mL). The layers are separated and theorganic layer washed successively with brine (100 mL), saturated NaHCO₃solution (300 mL), and brine (2×200 mL). The organic solution is driedover MgSO₄, filtered, and concentrated under reduced pressure.Purification of the product on silica gel (7:3 hexane:ethyl acetate)affords the desired amide 2a.

2b. 4(R)-benzyloxypyrrolidine-2(S)-carboxylic acid1,7-diphenyl-4-heptylamide

The amide 2a (9.04 g, 16.5 mmol) is dissolved in 160 mL of anhydrousdichloromethane. Trifluoroacetic acid (130 mL) is added dropwise over a5 minute period. After 45 minutes the mixture is cooled in an ice-bathand saturated K₂CO₃ solution is added until the pH is approximately 8.The mixture is transferred to a separatory funnel containingdichloromethane (300 mL) and water (300 mL) and shaken. The organiclayer is washed with water (100 mL) before drying over MgSO₄. Themixture is filtered and concentrated under reduced pressure to affordthe desired amine 2b.

2c.N-(3′,4′-Dimethoxyphenylsulfonyl)-4(R)-benzyloxypyrrolidine-2(S)-carboxylicacid 1,7-diphenyl-4-heptylamide

The amine 2b (5.65 g, 12.0 mmol) is taken up in anhydrous methylenechloride (100 mL) at room temperature. N,N-diisopropylethylamine (2.6mL, 15 mmol) is added and the solution is cooled to 5° C.3′,4′-Dimethoxyphenylsulfonyl chloride (3.5 g, 15 mmol) is added in oneportion. The reaction mixture is stirred for 18 hours at roomtemperature then concentrated to one-half volume. The concentrate ispoured onto ethyl acetate (300 mL) and washed successively with 0.1 MHCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine(50 mL). The organic solution is dried, filtered, and concentrated invacuo. Purification of the crude product by preparative chromatographyaffords the desired sulfonamide 2c.

EXAMPLE 3

3a. 2,3-Pyridinedicarboxylic acid bis(1-phenylbutylamide)

2,3-Pyridinedicarboxylic acid (3.0 g, 18.0 mmol) is combined with1-hydroxybenzotriazole (7.29 g, 54 mmol) at ambient temperature underinert atmosphere. Anhydrous DMF (150 mL) is added followed by4-phenylbutylamine (6.24 mL, 39 mmol), triethylamine (5.0 mL, 36 mmol),and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.61 g,45 mmol) in succession. The reaction mixture is stirred for 18 hours atambient temperature under inert atmosphere then poured onto ethylacetate (500 mL) and extracted successively with water (250 mL), 1N HCl(150 mL), and brine (100 mL). The organic solution is dried over MgSO₄,filtered, and concentrated under reduced pressure to afford the desiredbis-amide 3a.

3b. cis-2,3-Piperidinedicarboxylic acid bis(1-phenylbutylamide)

The bis-amide 3a (5.5 g, 12.8 mmol) is dissolved in absolute ethanol (50mL) at ambient temperature and transferred to a low pressurehydrogenation vessel containing Pearlman's catalyst (20 weight percentPd(OH)₂ on carbon, 1.0 g). The mixture is hydrogenated at 50 psi untilthe reduction is complete. The catalyst is removed by filtration througha pad of diatomaceous earth and the filtrate is concentrated underreduced pressure. Purification of the crude product by preparativechromatography (silica gel; gradient elution with 95:5:0.1 to 80:20:0.1methylene chloride:methanol:concentrated ammonium hydroxide) affords thedesired piperidine bis-amide 3b.

3c. N-(3′,4′-Dimethoxyphenylsulfonyl)-cis-2,3-piperidine dicarboxylicacid bis(1-phenylbutylamide)

The piperidine bis-amide 3b (2.12 g, 4.87 mmol) is taken up in anhydrousmethylene chloride (100 mL) at room temperature.N,N-Diisopropylethylamine (1.1 mL, 6 mmol) is added and the solution iscooled to 5° C. 3′,4′-Dimethoxyphenylsulfonyl chloride (1.4 g, 6 mmol)is added in one portion. The reaction mixture is stirred for 18 hours atroom temperature then concentrated to one-half volume. The concentrateis poured onto ethyl acetate (120 mL) and washed successively with 0.1 MHCl (40 mL), saturated sodium bicarbonate solution (40 mL), and brine(20 mL). The organic solution is dried, filtered, and concentrated invacuo. Purification of the crude product by preparative chromatographyaffords the desired sulfonamide 3c.

EXAMPLE 4

4a. Magnesium (40.2 g, 1.65 mol) and anhydrous ether (3.2 L) arecombined in a reaction vessel with stirring. A solution of1-bromo-3-phenyl propane in 1.6 L of anhydrous ether is added to anaddition funnel. The bromide solution is added dropwise to the stirringreaction vessel over a 1 hour period. Upon completion of addition, themixture stirs for 1-2 hours. A solution of 4-phenylbutyronitrile (160 g,1.1 mol) in anhydrous ether (2.4 L) is placed in the addition funnel.The solution is added to the reaction vessel over a 1 hour time period.Upon complete addition the solution is heated to reflux for 10 hours,and then stirs at room temperature for six hours.

4b. 1,7-Diphenyl-4-aminoheptane

The reaction mixture of 4a is diluted with methanol (3.2 L) using anaddition funnel. Sodium borohydride (83.4 g, 2.2 mol) is added inportions. Upon complete addition the reaction is stirred at roomtemperature for six hours. The reaction mixture is quenched by a slowaddition of water (3.2 L). The mixture is diluted with ether (3.2 L) andwater (1.6 L). The ether layer is separated and the aqueous layer isextracted twice with ether (3.2 L×2). The combined ether extracts arewashed once with sodium chloride solution, dried, filtered, andconcentrated in vacuo to give the crude product. This product is dilutedin ether (1.2 L) and acidified by slow addition of 1M HCl (1.2 L). Themixture stirs for one hour and is concentrated in vacuo. The resultingprecipitate is diluted with acetonitrile and is stirred for 16 hours.The desired 1,7-Diphenyl-4-aminoheptane 4b is collected by filtration.

Use of the Present Compounds

The compounds herein may be used for the treatment of such conditionsas, for example, treating hair loss in mammals, including arrestingand/or reversing hair loss and promoting hair growth. Such conditionsmay manifest themselves in, for example, alopecia, including malepattern baldness and female pattern baldness.

While certain of the present compounds may exhibit immunosuppressiveactivity, the preferred compounds of the present invention are, asdefined herein, non-immunosuppressive.

Furthermore, in addition to treating hair loss, the compounds of thepresent invention may be used to treat a variety of clinical conditionswhich include, but are not limited to, multi-drug resistance(particularly for use in cancer chemotherapy), neurological disordersand neurodegenerative diseases, cardiac injury associated withischemia/reperfusion injury, and treatment of fungal, microbial, viral(especially HIV), malarial or other parasitic diseases or conditions.The present compounds may also be useful as inhibitors of multi-drugtransporter proteins to enhance, for example, pharmacokinetics andbioavailability. Certain compounds of the present invention may exhibitimmunomodulatory properties. These compounds would prove useful in thetreatment of organ transplant rejection and various autoimmune diseaseswhich include, but are not limited to, Behcet's disease, Crohn'sdisease, systemic lupus erythematosus, psoriasis, rheumatoid arthritis,eczema, multiple sclerosis, myasthenia gravis, insulin-dependentdiabetes mellitus, and Graves' disease. In addition, the presentcompounds may have utility for the treatment of certain inflammatory andallergic disease states, including urticaria, allergic contactdermatitis, atopic dermatitis, atopic keratoconjunctivitis, inflammatorybowel disease, and asthma. The present compounds may also be useful inthe treatment of cardiac hypertrophy in congestive heart failure.

The present compounds may also be useful in combination with a matrixmetalloproteinase inhibitor for treatment of various conditionsincluding, for example, tissue destructive diseases mediated byexcessive metalloproteinase activity, cancer, and multi-drug resistance,as well as all of the conditions previously mentioned herein above.Particularly preferred matrix metalloproteinase inhibitors useful insuch combination include those described in U.S. patent application Ser.No. 60/024,765, Pikul et al., assigned to The Procter & Gamble Co.,filed Aug. 28, 1996, U.S. patent application Ser. No. 60/024,842,Natchus et al., assigned to The Procter & Gamble Co., filed Aug. 28,1996, U.S. patent application Ser. No. 60/024,846, Pikul et al.,assigned to The Procter & Gamble Co., filed Aug. 28, 1996, U.S. patentapplication Ser. No. 60/024,746, Almstead et al., assigned to TheProcter & Gamble Co., filed Aug. 28, 1996, U.S. patent application Ser.No. 60/024,830, Pikul et al., assigned to The Procter & Gamble Co.,filed Aug. 28, 1996, U.S. patent application Ser. No. 60/024,764, De etal., assigned to The Procter & Gamble Co., filed Aug. 28, 1996, U.S.patent application Ser. No. 60/024,764, De et al., assigned to TheProcter & Gamble Co., filed Aug. 28, 1996, and U.S. patent applicationSer. No. 60/024,766, Wang et al., assigned to The Procter & Gamble Co.,filed Aug. 28, 1996.

Preferably, the compounds of the present invention are formulated intopharmaceutical compositions for use in treatment or prophylaxis ofconditions such as the foregoing. Standard pharmaceutical formulationtechniques are used, such as those disclosed in Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990).

Typically, from about 5 mg to about 3000 mg, more preferably from about5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg,of a compound of the present invention is administered per day forsystemic administration. It is understood that these dosage ranges areby way of example only, and that daily administration can be adjusteddepending on various factors. The specific dosage of the compound to beadministered, as well as the duration of treatment, and whether thetreatment is topical or systemic are interdependent. The dosage andtreatment regimen will also depend upon such factors as the specificcompound used, the treatment indication, the efficacy of the compound,the personal attributes of the subject (such as, for example, weight,age, sex, and medical condition of the subject), compliance with thetreatment regimen, and the presence and severity of any side effects ofthe treatment.

In addition to the subject compound, the compositions of the subjectinvention contain a pharmaceutically-acceptable carrier (“carrier”). Theterm pharmaceutically-acceptable carrier, as used herein, means one ormore compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with a compound of thepresent invention, and with each other, in a manner such that there isno interaction which would substantially reduce the efficacy of thecomposition under ordinary use situations. Carriers must, of course, beof sufficiently high purity and sufficiently low toxicity to render themsuitable for administration to the animal, preferably mammal, beingtreated. The carrier can itself be inert or it can possesspharmaceutical benefits of its own.

The compositions of this invention may be in any of a variety of forms,suitable (for example) for oral, rectal, topical, nasal, ocular orparenteral administration. Of these, topical or oral administration isespecially preferred. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the activity ofthe compound of the present invention. The amount of carrier employed inconjunction with the compound is sufficient to provide a practicalquantity of material for administration per unit dose of the compound.Techniques and compositions for making dosage forms useful in themethods of this invention are described in the following references:Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2^(nd) Ed., (1976).

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

In particular, pharmaceutically-acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. These oral forms comprisea safe and effective amount, usually at least about 5%, and preferablyfrom about 25% to about 50%, of a compound of the present invention.Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed, containing suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquid oraldosage forms include aqueous solutions, emulsions, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules, and effervescent preparations reconstituted from effervescentgranules, containing suitable solvents, preservatives, emulsifyingagents, suspending agents, diluents, sweeteners, melting agents,coloring agents and flavoring agents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for oral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components depends onsecondary considerations like taste, cost, and shelf stability, whichare not critical for the purposes of the subject invention, and can bereadily made by a person skilled in the art.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically-acceptable carriers suitable forpreparation of such compositions are well known in the art. Typicalcomponents of carriers for syrups, elixirs, emulsions and suspensionsinclude ethanol, glycerol, propylene glycol, polyethylene glycol, liquidsucrose, sorbitol and water. For a suspension, typical suspending agentsinclude methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591,tragacanth and sodium alginate; typical wetting agents include lecithinand polysorbate 80; and typical preservatives include methyl paraben andsodium benzoate. Peroral liquid compositions may also contain one ormore components such as sweeteners, flavoring agents and colorantsdisclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

The compounds of the present invention may also be topicallyadministered. The carrier of the topical composition preferably aidspenetration of the present compounds into the skin to reach theenvironment of the hair follicle. Topical compositions of the presentinvention may be in any form including, for example, solutions, creams,ointments, gels, lotions, shampoos, leave-on and rinse-out hairconditioners, milks, cleansers, moisturizers, sprays, skin patches, andthe like.

Topical compositions containing the active compound can be admixed witha variety of carrier materials well known in the art, such as, forexample, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin Aand E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate,and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glycerylmonostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetylalcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate,iso-propyl palmitate, iso-propyl stearate, butyl stearate, polythyleneglycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachisoil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil,butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate,lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate;propellants, such as propane, butane, iso-butane, dimethyl ether, carbondioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylenechloride, iso-propanol, castor oil, ethylene glycol monoethyl ether,diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants,such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, solublecollagen, dibutyl phthalate, and gelatin; and powders, such as chalk,talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide,sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl arylammonium smectites, chemically modified magnesium aluminium silicate,organically modified montmorillonite clay, hydrated aluminium silicate,fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, andethylene glycol monostearate.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines. A preferred formulation fortopical delivery of the present compounds utilizes liposomes such asdescribed in Dowton et al., “Influence of Liposomal Composition onTopical Delivery of Encapsulated Cyclosporin A: 1. An in vitro StudyUsing Hairless Mouse Skin”, S.T.P. Pharma Sciences, Vol. 3, pp. 404-407(1993), Wallach and Philippot, “New Type of Lipid Vesicle: Novasome®”,Liposome Technology, Vol. 1, pp. 141-156 (1993), and Wallach, U.S. Pat.No. 4,911,928, assigned to Micro-Pak, Inc., issued Mar. 27, 1990.

The compounds of the present invention may also be administered byiontophoresis. See, e.g.,www.unipr.it/arpa/dipfarm/erasmus/erasm14.html, Banga et al.,“Hydrogel-based lontotherapeutic Delivery Devices for TransdermalDelivery of Peptide/Protein Drugs”, Pharm. Res., Vol. 10 (5), pp.697-702 (1993), Ferry L. L., “Theoretical Model of IontophoresisUtilized in Transdermal Drug Delivery”, Pharmaceutical Acta Helvetiae,Vol 70, pp. 279-287 (1995), Gangarosa et al., “Modern Iontophoresis forLocal Drug Delivery”, Int. J. Pharm, Vol. 123, pp. 159-171 (1995), Greenet al., “Iontophoretic Delivery of a Series of Tripeptides Across theSkin in vitro”, Pharm. Res., Vol 8, pp. 1121-1127 (1991), Jadoul et al.,“Quantification and Localization of Fentanyl and TRH Delivered byIontophoresis in the Skin”, Int. J. Pharm., Vol. 120, pp. 221-8 (1995),O'Brien et al., “An Updated Review of its Antiviral Activity,Pharmacokinetic Properties and Therapeutic Efficacy”, Drugs, Vol. 37,pp. 233-309 (1989), Parry et al., “Acyclovir Biovailability in HumanSkin”, J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992), Santi etal., “Drug Reservoir Composition and Transport of Salmon Calcitonin inTransdermal Iontophoresis”, Pharm. Res., Vol 14 (1), pp. 63-66 (1997),Santi et al., “Reverse Iontophoresis—Parameters DeterminingElectroosmotic Flow: I. pH and Ionic Strength”, J. Control. Release,Vol. 38, pp. 159-165 (1996), Santi et al., “ReverseIontophoresis—Parameters Determining Electroosmotic Flow: II. ElectrodeChamber Formulation”, J. Control. Release, Vol. 42, pp. 29-36 (1996),Rao et al., “Reverse Iontophoresis: Noninvasive Glucose Monitoring invivo in Humans”, Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995),Thysman et al., “Human Calcitonin Delivery in Rats by Iontophoresis”, J.Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994), Volpato et al.,“Iontophoresis Enhances the Transport of Acyclovir through Nude MouseSkin by Electrorepulsion and Electroosmosis”, Pharm. Res., Vol. 12 (11),pp. 1623-1627 (1995).

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules which can function in different ways to enhancehair growth effects of a compound of the present invention. Particularclasses of activity enhancers include other hair growth stimulants andpenetration enhancers.

Additional hair growth stimulants can be chosen from a wide variety ofmolecules which can function in different ways to enhance the hairgrowth effects of a compound of the present invention. These optionalother hair growth stimulants, when present, are typically employed inthe compositions herein at a level ranging from about 0.01% to about15%, preferably from about 0.1% to about 10%, most preferably from about0.5% to about 5% by weight of the composition.

Vasodilators such as potassium channel agonists including, for example,minoxidil and minoxidil derivatives such as aminexil and such as thosedescribed in U.S. Pat. Nos. 3,382,247, 5,756,092, issued May 26, 1998,U.S. Pat. No. 5,772,990, issued Jun. 30, 1998, U.S. Pat. No. 5,760,043,issued Jun. 2, 1998, U.S. Pat. No. 328,914, issued Jul. 12, 1994, U.S.Pat. No. 5,466,694, issued Nov. 14, 1995, U.S. Pat. No. 5,438,058,issued Aug. 1, 1995, and U.S. Pat. No. 4,973,474, issued Nov. 27, 1990,(all of which are herein incorporated by reference), and cromakalin anddiazoxide can be used as an additional hair growth stimulant in thecompositions herein.

One suitable class of additional hair growth stimulant for use hereinare antiandrogens. Examples of suitable antiandrogens may include, butare not limited 5-α-reductase inhibitors such as finasteride and thosedescribed in U.S. Pat. No. 5,516,779, issued May 14, 1996 (hereinincorporated by reference) and in Nane et al., Cancer Research 58,“Effects of Some Novel Inhibitors of C17,20-Lyase and 5α-Reductase invitro and in vivo and Their Potential Role in the Treatment of ProstateCancer,” as well as cyproterone acetate, azelaic acid and itsderivatives and those compounds described in U.S. Pat. No. 5,480,913,issued Jan. 2, 1996, flutamide, and those described in U.S. Pat. No.5,411,981, issued May 2, 1995, U.S. Pat. No. 5,565,467, issued Oct. 15,1996 and U.S. Pat. No. 4,910,226, issued Mar. 20, 1990, all of which areherein incorporated by reference.

Another suitable class of optional hair growth stimulants areimmunosuppressants or non-immunosuppressants such as 1) cyclosporin andcyclosporin analogs including those described in U.S. Provisional PatentApplication No. 60/122,925, Fulmer et al., filed Mar. 5, 1999, hereinincorporated by reference, and 2) FK506 analogs such as those describedin U.S. Provisional Patent Application No. 60/147,279, Degenhardt etal., filed Aug. 5, 1999; U.S. Provisional Patent Application No.60/147,313, Degenhardt et al., filed Aug. 5, 1999; U.S. ProvisionalPatent Application No. 60/147,280, Degenhardt et al., filed Aug. 5,1999; U.S. Provisional Patent Application No. 60/147,278, Degenhardt etal., filed Aug. 5, 1999; and U.S. Provisional Patent Application No.60/147,276, Eickhoff et al., filed Aug. 5, 1999; all of which are hereinincorporated by reference.

Another suitable class of optional hair growth stimulants areantimicrobials such as selenium sulfide, ketoconazole, triclocarbon,triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol,mipirocin and those described in EPA 0,680,745 (herein incorporated byreference), clinacycin hydrochloride, benzoyl peroxide, benzyl peroxideand minocyclin.

Anti-inflammatories can also be incorporated into the compositionsherein as an optional hair growth stimulant. Examples of suitableanti-inflammatories may include glucocorticoids such as hydrocortisone,mometasone furoate and prednisolone, nonsteroidal anti-inflammatoriesincluding cyclooxygenase or lipoxygenase inhibitors such as thosedescribed in U.S. Pat. No. 5,756,092, and benzydamine, salicylic acid,and those compounds described in EPA 0,770,399, published May 2, 1997,WO 94/06434, published Mar. 31, 1994, and FR 2,268,523, published Nov.21, 1975, all of which are herein incorporated by reference.

Another suitable class of optional hair growth stimulants are thyroidhormones and derivatives and analogs thereof. Examples of suitablethyroid hormones for use herein may include triiodothyrionine. Examplesof thyroid hormone analogs which may be suitable for use herein includethose described in U.S. Provisional Patent Application No. 60/136,996,Zhang et al., filed Jun. 1, 1999, U.S. Provisional Patent ApplicationNo. 60/137,024, Zhang et al., filed Jun. 1, 1999, U.S. ProvisionalPatent Application No. 60/137,022, Zhang et al., filed Jun. 1, 1999,U.S. Provisional Patent Application No. 60/137,023, Zhang et al., filedJun. 1, 1999, U.S. Provisional Patent Application No. 60/137,052,Youngquist et al., filed Jun. 1, 1999, U.S. Provisional PatentApplication No. 60/137,063, Youngquist et al., filed Jun. 1, 1999, andU.S. Provisional Patent Application No. 60/136,958, Youngquist et al.,filed Jun. 1, 1999.

Prostaglandin agonists or antagonists can also be used as optional hairgrowth stimulants in the compositions herein. Examples of suitableprostaglandins agonists or antagonists include latanoprost and thosedescribed in WO 98/33497, Johnstone, published Aug. 6, 1998, WO95/11003, Stjernschantz, published Apr. 27, 1995, JP 97-100091, Ueno andJP 96-134242, Nakamura.

Another class of optional hair growth stimulants for use herein areretinoids. Suitable retinoids may include isotretinoin, acitretin, andtazarotene.

Another class of optional hair growth stimulants for use herein aretriterpenes such as, for example, those disclosed in Bradbury et al.,U.S. patent application Ser. No. 09/353,408, “Method for Regulating HairGrowth”, filed Jul. 15, 1999 and Bradbury et al., U.S. patentapplication Ser. No. 09/353,409, “Compositions Which Contain Triterpenesfor Regulating Hair Growth”, filed Jul. 15, 1999, each incorporated byreference in their entirety.

Other classes of optional hair growth stimulants for use herein includeflavinoids, ascomycin derivatives and analogs, histamine antagonistssuch as diphenhydramine hydrochloride, other triterpenes such asoleanolic acid and ursolic acid and those described in U.S. Pat. No.5,529,769, JP 10017431, WO 95/35103, U.S. Pat. No. 5,468,888, JP09067253, WO 92/09262, JP 62093215, U.S. Pat. Nos. 5,631,282, 5,679,705,JP 08193094, saponins such as those described in EP 0,558,509 to Bonteet al., published Sep. 8, 1993 and WO 97/01346 to Bonte et al, publishedJan. 16, 1997 (both of which are herein incorporated by reference intheir entirety), proteoglycanase or glycosaminoglycanase inhibitors suchas those described in U.S. Pat. No. 5,015,470, issued May 14, 1991, U.S.Pat. No. 5,300,284, issued Apr. 5, 1994 and U.S. Pat. No. 5,185,325,issued Feb. 9, 1993 (all of which are herein incorporated in theirentirety by reference) estrogen agonists and antagonists, pseudoterins,cytokine and growth factor promoters, analogs or inhibitors such asinterleukin1 inhibitors, interleukin-6 inhibitors, interleukin-10promotors, and tumor necrosis factor inhibitors, vitamins such asvitamin D analogs and parathyroid hormone antagonists, Vitamin B12analogs and panthenol, interfuron agonists and antagonists, hydroxyacidssuch as those described in U.S. Pat. No. 5,550,158, benzophenones, andhydantoin anticonvulsants such as phenytoin.

Other additional hair growth stimulants are described in detail in, forexample, JP 09-157,139 to Tsuji et al., published Jun. 17, 1997; EP0277455 A1 to Mirabeau, published Aug. 10, 1988; WO 97/05887 to CaboSoler et al., published Feb. 20, 1997; WO 92/16186 to Bonte et al.,published Mar. 13, 1992; JP 62-93215 to Okazaki et al., published Apr.28, 1987; U.S. Pat. No. 4,987,150 to Kurono et al., issued Jan. 22,1991; JP 290811 to Ohba et al., published Oct. 15, 1992; JP 05-286,835to Tanaka et al., published Nov. 2, 1993, FR 2,723,313 to Greff,published Aug. 2, 1994, U.S. Pat. No. 5,015,470 to Gibson, issued May14, 1991, U.S. Pat. No. 5,559,092, issued Sep. 24, 1996, U.S. Pat. No.5,536,751, issued Jul. 16, 1996, U.S. Pat. No. 5,714,515, issued Feb. 3,1998, EPA 0,319,991, published Jun. 14, 1989, EPA 0,357,630, publishedOct. 6, 1988, EPA 0,573,253, published Dec. 8, 1993, JP 61-260010,published Nov. 18, 1986, U.S. Pat. No. 5,772,990, issued Jun. 30, 1998,U.S. Pat. No. 5,053,410, issued Oct. 1, 1991, and U.S. Pat. No.4,761,401, issued Aug. 2, 1988, all of which are herein incorporated byreference.

Non-limiting examples of penetration enhancers which may be used in thecompositions herein include, for example, 2-methyl propan-2-ol,propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, POE(2) ethylether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2)methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid,propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propyleneglycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol,POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyladipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate,dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate,dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate,dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate,dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate,ethyl salicylate, iso-propyl palmitate, ethyl laurate, 2-ethyl-hexylpelargonate, iso-propyl isostearate, butyl laurate, benzyl benzoate,butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butylstearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hyroxyoctanoicacid, dimethyl sulphoxide, N,N-dimethyl acetamide, N,N-dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone,5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone,1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters,tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and,1-dodecylazacyloheptan-2-one.

In all of the foregoing, of course, the compounds of the invention canbe administered alone or as mixtures, and the compositions may furtherinclude additional drugs or excipients as appropriate for theindication.

Composition Examples

The following composition and method examples do not limit theinvention, but provide guidance to the skilled artisan to prepare anduse the compounds, compositions, and methods of the invention. In eachexample, a compound of the present invention other than the onementioned may be substituted in the example with similar results.

EXAMPLE A

A tablet for oral administration according to the present invention ismade, comprising:

Component Amount Compound of Example 3  15 mg Lactose 120 mg MaizeStarch  70 mg Talc  4 mg Magnesium Stearate  1 mg

A human female subject weighing 60 kg (132 lbs), suffering fromrheumatoid arthritis, is treated by a method of this invention.Specifically, for two years, a regimen of three tablets per day of theabove composition is administered orally to the subject.

EXAMPLE B

A composition for topical administration according to the presentinvention is made, comprising:

Component Amount Compound of Example 1  5% Ethanol 57% Propylene Glycol19% Dimethyl Isosorbide 19%

A human male subject suffering from male pattern baldness is treated bya method of this invention. Specifically, for 6 weeks, the abovecomposition is daily administered topically to the subject.

EXAMPLE C

A composition for topical administration according to the presentinvention is made according to the method of Dowton et al., “Influenceof Liposomal Composition on Topical Delivery of Encapsulated CyclosporinA: I. An in vitro Study Using Hairless Mouse Skin”, S.T.P. PharmaSciences, Vol. 3, pp. 404-407 (1993), using the compound of Example 2 inlieu of cyclosporin A and using the Novasome 1 for the non-ionicliposomal formulation.

A human male subject suffering from male pattern baldness is treatedeach day with the above composition. Specifically, for 6 weeks, theabove composition is administered topically to the subject.

EXAMPLE D

A shampoo according to the present invention is made, comprising:

Component Ex. C-1 Ex. C-2 Ex. C-3 Ex. C-4 Ammonium Lauryl Sulfate 11.5%11.5% 9.5% 7.5% Ammonium Laureth Sulfate 4% 3% 2% 2% Cocamide MEA 2% 2%2% 2% Ethylene Glycol Distearate 2% 2% 2% 2% Cetyl Alcohol 2% 2% 2% 2%Stearyl Alcohol 1.2% 1.2% 1.2% 1.2% Glycerin 1% 1% 1% 1% Polyquaternium10 0.5% 0.25% — — Polyquaternium 24 — — 0.5% 0.25% Sodium Chloride 0.1%0.1% 0.1% 0.1% Sucrose Polyesters of Cottonate 3% 3% — — Fatty AcidSucrose Polyesters of Behenate 2% 3% — — Fatty Acid PolydimethylSiloxane — — 3% 2% Cocaminopropyl Betaine — 1% 3% 3% Lauryl DimethylAmine Oxide 1.5% 1.5% 1.5% 1.5% Decyl Polyglucose — — 1% 1% DMDMHydantoin 0.15% 0.15% 0.15% 0.15% Compound of Example 1 2% — — —Compound of Example 2 — 5% — — Compound of Example 3 — — 3% —Phenoxyethanol 0.5% 0.5% 0.5% 0.5% Fragrance 0.5% 0.5% 0.5% 0.5% Waterq.s. q.s. q.s. q.s.

What is claimed is:
 1. A compound having a structure:

and pharmaceutically acceptable salts, hydrates, and biohydrolyzableamides, esters, and imides thereof, wherein: (a) G is selected from thegroup consisting of alkyl having at least 3 carbon atoms, alkenyl,heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; (b) Z isa saturated or unsaturated 4-, 5-, 6-, 7-, 8-, or 9-membered heterocycleoptionally containing one or more additional heteroatoms selected fromthe group consisting of O, N, S, S(O), S(O)₂, and P((O)OK); (c) K isselected from the group consisting of hydrogen, alkyl, alkenyl,heteroalkyl, heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl,arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; (d) W isselected from the group consisting of nil, hydrogen, and lower alkyl;(e) A is selected from the group consisting of nil and alkyl; (f) Y isselected from the group consisting of N, O, and S; (g) R₂ and R₃ areeach, independently, selected from the group consisting of nil,hydrogen, alkyl, and arylalkyl; (h) R₄ is selected from the groupconsisting of methylene and methyne; (i) R₅ and R₆ are each,independently, selected from the group consisting of nil, hydrogen,alkyl having at least three carbon atoms, alkenyl, heteroalkyl,heteroalkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,heteroarylalkyl, arylalkenyl, and heteroarylalkenyl; or wherein R₅ andR₆ are bonded together to form a carbocyclic or hetercyclic ring;wherein at least one of R₅ or R₆ is not nil or hydrogen; (j) Q isselected from the group consisting of CH₂, CHR₉, NR₉, S, S(O), andS(O)₂; (k) R₉ and R₁₀ are each, independently, selected from the groupconsisting of nil, hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl,cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl,arylalkenyl, heteroarylalkenyl, halo, cyano, hydroxy, oxo, imino,—R₁₄SR₁₅, —R₁₄S(O₂)R₁₅, —R₁₄S(O)R₁₅, —R₁₄C(O)R₁₅, —R₁₄C(O)NR₁₅R₁₆,—R₁₄C(O)OR₁₅, —R₁₄OR₁₅, —R₁₄NR₁₅R₁₆, —R₁₄P(O)NR₁₅R₁₆, —R₁₄P(O)OR₁₅R₁₆,and a spiro moiety; (l) R₇ and R₈ are bonded together to form anaromatic or saturated, carbocyclic or heterocyclic ring wherein the ringis fused to Z; (m) R₁₄ is selected from the group consisting of nil,alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, andheteroarylalkenyl; (n) R₁₅ is selected from the group consisting ofhydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, cycloalkyl,heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, arylalkenyl, andheteroarylalkenyl; and (o) R₁₆ is selected from the group consisting ofhydrogen and alkyl.
 2. A compound according to claim 1 wherein Z is a5-, 6-, or 7-membered heterocycle wherein W is hydrogen.
 3. A compoundaccording to claim 2 wherein Z is a 5-membered heterocycle, A is nil, Yis N, and R₂ is hydrogen.
 4. A compound according to claim 3 wherein Gis substituted phenyl.
 5. A compound according to claim 4 wherein R₇ andR₈ are bonded together to form a 5-, 6-, or 7-membered carbocyclic orheterocyclic aromatic ring which is fused to Z.
 6. A compound accordingto claim 5 which is selected from the group consisting of:

wherein R₁₈, R₁₉, and R₂₀ are each, independently, selected from thegroup consisting of hydrogen, alkoxy, hydroxy, nitro, amino, alkylamino,cyano, halo, carboxy, thiol, imino, and aryloxy.
 7. A compound accordingto claim 6 which is selected from the group consisting of:

wherein R₃₀ is selected from the group consisting of —OR₃₂ and—OCH₂C(O)OR₃₂, wherein R₃₂ is selected from the group consisting ofhydrogen and alkyl, and wherein R₃₅ is selected from the groupconsisting of hydrogen and —OR₃₆, wherein R₃₆ is selected from the groupconsisting of hydrogen and alkyl.
 8. A compound according to claim 2wherein Z is a 6-membered heterocycle and wherein A is nil, Y is N, andR₂ is hydrogen.
 9. A compound according to claim 8 wherein G issubstituted phenyl.
 10. A compound according to claim 9 which isselected from the group consisting of:

wherein R₁₈, R₁₉, and R₂₀ are each, independently, selected from thegroup consisting of hydrogen, alkoxy, hydroxy, nitro, amino, alkylamino,cyano, halo, carboxy, thiol, imino, and aryloxy.
 11. A compoundaccording to claim 10 which is selected from the group consisting of:

wherein R₃₀ is selected from the group consisting of —OR₃₂ and—OCH₂C(O)OR₃₂, wherein R₃₂ is selected from the group consisting ofhydrogen and alkyl, and wherein R₃₅ is selected from the groupconsisting of hydrogen and —OR₃₆, wherein R₃₆ is selected from the groupconsisting of hydrogen and alkyl.
 12. A compound according to claim 8which is selected from the group consisting of:


13. A composition comprising a compound according to claim 1 and apharmaceutically-acceptable carrier.
 14. A method of treating hair losscomprising administering to a mammal a composition according to claim13.
 15. A method according to claim 14 wherein the administration istopical.
 16. A method according to claim 14 wherein the administrationis oral.
 17. A method of treating or preventing multi-drug resistancecomprising administering to a mammal a composition according to claim13.
 18. A composition according to claim 13 additionally comprising amatrix metalloproteinase inhibitor.
 19. A compound according to claim 8,wherein the structure is selected from the group consisting of: